PROJECT SUMMARY ? OVERVIEW ABSTRACT Here we describe our vision for the National Center for the Identification and Study of Individuals with Atypical Diabetes Mellitus in response to RFA-DK-17-006. The Center?s purpose is to convene key diabetes centers with expertise in the clinical assessment, genetics, and physiological study of diabetes as institutional foci of a nation-wide call for subjects with atypical forms of diabetes designed to: a) Foster the study of individuals with rare/atypical forms of diabetes mellitus of unknown cause; b) Identify and analyze phenotypic and genotypic defects that may provide insights into more common, heterogeneous forms of type 2 diabetes mellitus (T2DM) in the general population; and c) Develop a community resource to advance research in this area through a database to facilitate the collection and dissemination of phenotypic and genetic data with biorepository samples and a living biobank for access by the diabetes research community. Our central hypothesis is that the identification and study of new cases of rare/atypical forms of diabetes will yield greater insights into the etiology and genetic heterogeneity of T2DM. The Center, building on the track records of the participating groups over the last three decades, will support primary research endeavors to: i. Build on our existing monogenic diabetes resources, genetics expertise, and deep knowledge of the biology of diabetes to develop and implement processes (based on pedigree analysis and strategic whole exome sequencing) for identifying and studying individuals/families with rare and uncharacterized forms of diabetes; ii. Create a national network of collaborators to help ascertain and initially phenotype the individuals in pedigrees identified; iii. Adapt our existing REDCap-based monogenic diabetes database to create and manage a study database for rare/atypical forms of diabetes, a living biobank and biospecimen repository, and a public portal for use by the diabetes research community in future studies; and iv. Facilitate future investigation of the impact of genetic variation by providing access to biobanked materials and the living biobank. Detailed phenotyping, genotyping, and gene sequencing of these individuals and their families will help to characterize rare atypical subtypes present in the spectrum of T2DM in the general population, and reveal novel mechanistic pathways involved in the pathogenesis of diabetes. Knowledge of the pathways and their constituent molecules should point to novel strategies for the treatment and/or prevention of T2DM.